1. Field of the Invention
The present invention is drawn to compositions comprising conjugates of an anticancer agent such as gemcitabine or docetaxel and/or a targeting ligand such as RGDfK, EPPT1 peptide or folate to N-(2-hydroxypropyl)methacrylamide (HPMA), and with methods for delivering those conjugates to a cell utilizing said compositions.
2. Background of the Invention
Docetaxel (Taxotere®) is a member of one of the most important new classes of oncology drugs. However, its poor solubility presents pharmaceutical challenges, and emerging data suggest that specific tissue exposure profiles, such as low drug concentrations for extended times, can enhance beneficial antitumor mechanisms. As the main disadvantage of docetaxel is that it is highly lipophilic and practically insoluble in water, formulation considerations for docetaxel have been studied extensively. For clinical use, it is formulated and administered in a cosolvent system. The drug is packaged at 40 mg/ml in polysorbate-80 (USPDI). Prior to use, it is diluted to 10 mg/ml with a solution containing 13% (v/v) ethanol in water. Before administration, the drug is further diluted in 250 ml saline or dextrose, achieving a final concentration of 0.3-0.9 mg/liter. The solution is used within 4 h. Some apparently unique adverse effects are associated with docetaxel formulation. Delayed-onset pleural effusions and edema have led in some cases to the discontinuation of treatment. Because of the toxicities associated with the cosolvents required for taxane administration, a variety of alternative compositions of docetaxel including synthesis of docetaxel analogues, entrapment in liposomes and preparation of polymer-docetaxel conjugates have been investigated. With respect to the preparation of polymer-docetaxel conjugates, some polymers have been proposed including poly(amino acid)s (WO/2007/067417) and synthetic polymers such as poly(ethylene glycol) (PEG).
In the past few years, gemcitabine (Gemzar®), a novel pyrimidine nucleoside analogue, has become the standard chemotherapeutic agent used in patients with pancreatic cancer. Pancreatic adenocarcinoma is the fourth leading cause of cancer death in the United States. Nationwide, 28,000 new cases are diagnosed annually. Chemotherapy and radiation therapy are largely ineffective, and metastatic disease frequently develops even after potentially curative surgery. The 1-year survival rate of this cancer is 20%, and the 5-year survival rate is only 1-3%. Not more than 25% of patients with pancreatic cancer will benefit from gemcitabine. Clearly, an effective treatment for this devastating disease is urgently needed. To increase the benefit of gemcitabine in cancer patients, the new and first formulation of polymer-gemcitabine conjugate is disclosed in this invention.
In light of the foregoing, there is a high unmet need in the art for modifications of docetaxel and gemcitabine that can retain or increase its activity with tumor specificity while reducing its toxicity.